Regulation of fear expression by activity-dependent BDNF in direct hippocampal-to-prelimbic projections

活动依赖性 BDNF 在直接海马到前边缘投射中对恐惧表达的调节

基本信息

批准号：
10220675
负责人：
HENRY HALLOCK
金额：
$ 7.26万
依托单位：
LIEBER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220675
关键词：
Address Affect Anatomy Area Behavior Brain Brain region Brain-Derived Neurotrophic Factor Calcium Cell physiology Chronic Data Disease Enterobacteria phage P1 Cre recombinase Frequencies Fright Functional disorder Generalized Anxiety Disorder Genes Genetic Transcription Goals Head Hippocampus (Brain)Human Image Impairment Implant In Situ Hybridization Label Laboratories Link Literature Medial Mediating Membrane Potentials Microscope Molecular Mus Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Pattern Pharmacological Treatment Population Population Dynamics Post-Traumatic Stress Disorders Prefrontal Cortex Process Production Rattus Regulation Reporter Research Rest Rodent Role Signal Transduction Specificity Structure Symptoms Synaptic Potentials Techniques Testing Therapeutic Viral Virus Work behavioral phenotyping calcium indicator cell type clinically relevant experimental study innovation lens molecular phenotype mutant neural circuit neuromechanism neuronal patterning neuropsychiatric disorder neurotrophic factor novel overexpression patch clamp precision medicine retrograde transport side effect single molecule therapeutic target therapy development treatment strategy

项目摘要

Abnormalities in hippocampal-prefrontal function are associated with impairments in fear regulation in humans, rats, and mice. Despite the known associations between function in these brain regions and fear expression, there is a fundamental gap in our understanding of how dysfunction in this circuit leads to expression deficits. Continued existence of this gap represents an important problem because a thorough understanding of how anatomically-defined neural circuits contribute to fear will likely be critical for the development of treatments for disorders featuring dysregulation of fear expression. The long-term goal is to better understand how altered molecular and cellular function in anatomically-connected populations of neurons contributes to fear dysregulation in neuropsychiatric disorders, and to use this information to develop novel treatment strategies for these disorders by selectively targeting clinically-relevant molecules within these populations. The overall objective of this proposal, and the first step toward our long-term goal, is to establish a causal link between one such molecule, brain-derived neurotrophic factor (BDNF), fear expression, and an anatomically-connected neural circuit, comprised of ventral hippocampal (vHC) neurons with direct projections to the prelimbic cortex (PrL), or vHC-PrL projectors. Our central hypothesis is that BDNF signaling impacts the ability of vHC-PrL projectors to bi-directionally regulate fear expression. The rationale for the proposed research is that, once causal links between hippocampal-prefrontal function, Bdnf, and fear expression are established, the selective manipulation of Bdnf in the hippocampal-prefrontal pathway will lead to therapeutic approaches to fear dysregulation that target only the affected neural circuitry. The central hypothesis of the proposal will be tested by pursuing three Specific Aims: 1) Examine how altered activity-dependent BDNF signaling impacts the structure and function of vHC-PrL projectors, 2) determine whether over-expression of BDNF in vHC-PrL projectors reverses fear-related behavioral and molecular phenotypes in the PrL of mice with impaired hippocampal-prefrontal function, and 3) investigate how aberrant BDNF-dependent plasticity impacts population dynamics in the prelimbic cortex during fear expression. The approach is innovative because it investigates the role of a selective neural circuit in fear expression with heretofore impossible anatomical specificity; furthermore, it proposes the use of cutting edge techniques to causally link Bdnf with function of this circuit during fear expression and fear-related population dynamics, which has never before been done. The proposed research is significant because the results are expected to vertically advance our understanding of the neural circuitry underlying fear expression, as well as provide potential avenues for anatomically-localized therapeutic targeting in disorders featuring fear dysregulation. It is likely that such selective targeting of neural circuitry in these disorders will be efficacious in reducing both the symptoms of these disorders and the side effects associated with current pharmacological treatments, which act non-specifically in the brain.

海马前额外功能的异常与人类恐惧调节的损害有关，老鼠和老鼠。尽管这些大脑区域的功能与恐惧表达之间有已知的关联，但我们了解该电路中功能障碍如何导致表达缺陷存在根本差距。持续存在这一差距是一个重要的问题，因为对解剖学定义的神经回路有助于恐惧，对于开发治疗的恐惧至关重要恐惧表达失调的疾病。长期目标是更好地了解如何改变解剖连接神经元中的分子和细胞功能有助于恐惧神经精神疾病的失调，并使用这些信息来制定新颖的治疗策略对于这些疾病，通过选择性地靶向这些人群中临床上的分子。总体该提案的目的以及朝着我们长期目标迈出的第一步是建立一个因果关系这种分子，脑衍生的神经营养因子（BDNF），恐惧表达和解剖连接神经电路，由腹侧海马（VHC）神经元组成，直接投射到前皮层（PRL）或VHC-PRL投影仪。我们的中心假设是BDNF信号传导影响VHC-PRL的能力双向调节恐惧表达的投影仪。拟议研究的理由是，一次建立了海马 - 前额外功能，BDNF和恐惧表达之间的因果关系，选择性在海马前额外途径中对BDNF操纵将导致恐惧的治疗方法仅针对受影响神经回路的失调。该提案的中心假设将进行测试通过追求三个具体目的：1）检查活动依赖性BDNF信号传导如何影响 VHC-PRL投影仪的结构和功能，2）确定BDNF在VHC-PRL中的过表达是否过表达投影仪逆转了与恐惧相关的行为和分子表型的小鼠PRL 海马前额外功能和3）研究如何影响BDNF依赖性可塑性如何影响恐惧表达期间，前皮层中的种群动态。这种方法是创新的，因为它研究选择性神经回路在恐惧表达中的作用，迄今为止不可能解剖特异性；此外，它建议使用尖端技术将BDNF与此功能联系起来恐惧表达和与恐惧相关的人口动态时的巡回赛，这从未做过。这拟议的研究很重要，因为期望结果垂直提高我们对恐惧表达的基础神经回路，并为解剖学上的潜在途径提供了潜在的途径患有恐惧失调的疾病的治疗靶向。这种选择性靶向神经很可能这些疾病中的电路将有效减少这些疾病的症状和侧面的症状与当前药理治疗相关的影响，这些治疗在大脑中非特异性起作用。